We have developed an innovative dosage form for vaginal drug delivery using polymeric fibers fabricated by electrospinning. Drug-eluting fibers exhibit unique materials and processing features that distinguish them from existing microbicide products. Our work to date has shown the versatility of polymer fibers for rapid and sustained delivery of diverse ARV drugs alone and in combination, to fabricate composite materials of varying microstructure, and to be produced using a manufacturing-scale electrospinning process. However, the further advancement and development of any single microbicide drug delivery system must prioritize that the product embody physical attributes that impact user perceptions without compromising the design for biological efficacy. While our previous results advance the concept of using drug-eluting fibers as a new dosage form for topical delivery of combination ARV drugs for HIV prevention, the feasibility of this new platform technology to be designed for chemoprophylactic protective efficacy against vaginal HIV challenge while exhibiting bulk material properties with adequate user perceptibility (geometry, texture, dissolution time and viscosity) has not been demonstrated. We propose here a project framework to inform the design of a first-generation fiber-based topical microbicide that is constrained for functions prioritized from user perception and NHP safety/PK studies. This proposal integrates three primary research areas: (i) Fiber DDS prototype design and formulation; (ii) User-guided product design and evaluation, and (iii) NHP safety/PK and efficacy testing. Our framework is an iterative process to design, test, and select lead candidate fiber DDS prototypes that are optimized for user perceptions (Aim 1) and biological safety/PK (Aim 2), before advancing to a vaginal challenge efficacy study in NHPs (Aim 3). We selected a novel triple ARV drug combination to demonstrate the strength of the fiber DDS to deliver agents that are physico-chemically diverse, have differing mechanisms of action against HIV, and show instantaneous inhibitory potential in combination to halt virus replication. We also propose to design fiber fabrics that modulate drug release for both pericoital and sustained protection. Finally, we incorporate incisive product acceptability studies early in the preclinical development of a new microbicide product to help guide the design of the formulation's biophysical and other attributes to have the greatest impact on user adherence. These studies will be the first to confirm that fiber-base microbicides can be designed to prioritize physical properties that are critical to the user experience, while at the same time prioritizing functional properties that prevent vaginal HIV infection. The broader impact of these innovations will support the rapid advancement of a fiber microbicide to first-in-human clinical trials.